The long-range goal of this project is to determine the effects of diabetes and the hypoglycemic consequences of intensive therapy on in vivo brain glucose metabolism in humans. The brain is critically dependent on glucose to maintain normal function. In recent years it has become apparent that patients with type 1 diabetes (T1DM), recurrent hypoglycemia, and hypoglycemia unawareness (HU) develop compensatory mechanisms that prevent them from detecting a fall in blood glucose concentration. The underlying mechanisms responsible for-HI) are unknown, but an alteration in glucose transport and/or metabolism or a change in brain glycogen metabolism are two possible explanations. To better understand how alterations in brain glucose and glycogen metabolism may contribute to the development of HU, we propose to use NMR methods to address the following aims and hypotheses: Aim #1: To determine whether successful islet transplantation will normalize the elevated brain glucose concentration and the blunted counterregulatory hormone/symptom responses to hypoglycemia present in patients with T1DM, recurrent hypoglycemia, and HU. Hypothesis #1: Brain glucose concentrations measured under controlled conditions will be lower and the counterregulatory hormone/symptom responses to hypoglycemia will be greater in patients with T1DM, recurrent hypoglycemia, and HU after as opposed to before successful islet transplantation. Aim #2: To determine if brain glycogen content increases in the human brain following hypoglycemia. Hypothesis #2: The rates of 13C glucose incorporation into brain glycogen and brain glycogen content will be higher following hypoglycemia than following euglycemia. Aim #3: To determine if brain glycogen content decreases in the human brain during hypoglycemia. Hypothesis #3: The rate of glycogen degradation as measured by will be higher during hypoglycemia than during euglycemia. Aim #4: To determine if brain glycogen content is higher in subjects with T1DM, recurrent hypoglycemia, and HU than in controls. Hypothesis #4: Brain glycogen content will be higher in subjects with T1DM, recurrent hypoglycemia and HU than in controls. Relevance: This work is highly relevant to patients with diabetes because it will provide important insights into how the brain maintains energy metabolism during and in response to hypoglycemia. This vital information will be used to improve the care of patients with diabetes.